MANAGEMENT OF UNCOMPLICATED URINARY TRACT INFECTIONS

Urinary tract infections can be classified by anatomic site of involvement into lower and upper urinary tract
infections. Infections of the lower urinary tract include cystitis, urethritis, prostatitis, and epididymitis, and
those of the upper urinary tract include pyelonephritis.
Urinary tract infections may be further classified as complicated or uncomplicated.
In women with a structurally and functionally normal urinary tract, cystitis and pyelonephritis are
considered uncomplicated urinary tract infections.
Urinary tract infections in men, elderly people, pregnant women, or patients who have an indwelling
catheter or an anatomic or functional abnormality are considered complicated urinary tract infections.

ETIOLOGY

Risk factors for urinary tract infections in women include frequent sexual intercourse, lack of urination after
intercourse, use of a diaphragm, use of a spermicide, and a history of recurrent urinary tract infections.

As many as 80% of uncomplicated urinary tract infections are caused by Escherichia coli, followed by
Staphylococcus saprophyticus in as many as 5% to 15% of cases. Enterococci, Klebsiella species and Proteus
mirabilis account for a small percentage of overall infections.7

OVERVIEW OF ANTIBIOTICS

The antimicrobial agents most commonly used to treat uncomplicated urinary tract infections include the
combination drug trimethoprim and sulfamethoxazole, trimethoprim, -lactams, fluoroquinolones,
nitrofurantoin, and fosfomycin tromethamine.

These agents are used primarily because of their tolerability, spectrum of activity against suspected
uropathogens, and favorable pharmacokinetic profiles. In the treatment of urinary tract infections, the
resolution of bacteriuria has been correlated with the concentration of the antimicrobial agent in the urine rather
than serum levels. All the antimicrobial agents approved for the treatment of urinary tract infections achieve
inhibitory urinary concentrations that significantly exceed serum levels.

TREATMENT

The goal of antimicrobial therapy is to eliminate the infecting organisms from the urinary tract and provide the
resolution of symptoms. Table 1 lists the drugs, their dosages. Clinicians should consider many factors when
selecting an antibiotic for a urinary tract infection, such as the patient's allergy history, the cost and tolerability
of the treatment, previous antibiotic therapy, and most important, the prevalence of resistance in the community.

Antibiotic therapy for urinary tract infections

Drug Dose, mg Frequency Duration, days

Sulfonamides
TMP-SMX 160/800 2/day 3
TMP 100 2/day 3
Fluoroquinolones
Norfloxacin (Noroxin) 400 2/day 3
Ciprofloxacin HCl (Cipro) 100-250 2/day 3
Levofloxacin (Levaquin) 250-500 Daily 3
Nitrofurantoin macrocrystals
(Macrodantin) 100 4/day 7
(Macrobid) 100 2/day 7
-Lactams
Cefpodoxime (Vantin) 100 2/day 3
Cefixime (Suprax) 400 Daily 3
Cephalexin 250-500 4/day 3
Amoxicillin 250-500 3/day 3
Miscellaneous
Fosfomycin tromethamine (Monurol) 3,000 (3 g) Daily 1
.

Single-dose regimens

Although single-dose therapy using -lactams, trimethoprim-sulfamethoxazole, trimethoprim, and

fluoroquinolones have shown high cure rates, single-dose therapy is associated with a high rate of
recurrence within 6 weeks of initial treatment. Reinfection may be due to the failure of single-dose treatment
to eradicate gram-negative pathogens from the perianal area. Aminopenicillins and first-generation
cephalosporins have shorter half-lives, which may contribute to their lower efficacy compared with other
agents.

Short-course therapy

Controlled trials of uncomplicated urinary tract infections have demonstrated that therapy for 3 days provided
similar eradication rates and a lower incidence of side effects compared with 7 to 10 days of therapy. The
guidelines of the Infectious Disease Society of America also concluded that 3-day regimens of trimethoprim,
trimethoprim-sulfamethoxazole, and fluoroquinolones were more effective than single-dose regimens and that
single-or 3-day regimens were better tolerated than longer regimens (7-10 days). Patients who may require 7
days of therapy include pregnant women, patients with diabetes mellitus, and those with symptoms lasting
longer than 1 week. For uncomplicated cystitis, treatment with trimethoprim-sulfamethoxazole, trimethoprim, or
fluoroquinolones for 3 days should result in an eradication rate of greater than 90% with a low incidence of
adverse effects.

RECURRENT URINARY TRACT INFECTIONS

Patients with three or more infections per year should be offered either continuous low-dose antibiotic
prophylaxis, patient-initiated, or postcoital prophylaxis if the onset of infection is linked to sexual intercourse.
Before a prophylactic regimen is chosen, a urine culture should be performed to determine the susceptibility of
the pathogen. The duration of continuous prophylactic therapy is usually 6 months to a year. Unfortunately,
within 6 months of discontinuing antibiotic prophylaxis, 40% to 60% of women develop a urinary tract
infection, and prophylaxis must be resumed.

Antibiotic prophylaxis regimens for recurrent infections

Drug Dosage
Continuous daily prophylaxis for 6 mo
TMP-SMX 40/200 mg* nightly or 3 /wk
TMP-SMX 100 mg nightly
Nitrofurantoin 50-100 mg nightly
Norfloxacin 200 mg a day
Cephalexin 250 mg a day
Postcoital prophylaxis
TMP-SMX 40/200 mg*
Nitrofurantoin 50-100 mg
Cephalexin 250 mg
TMP-SMX = trimethoprim-sulfamethoxazole.
*
Half of a single-strength tablet.

Must be temporal in nature.

Complicated UTI (acute pyelonephritis)

Empiric parenteral treatment after culture with:

Ampicillin plus aminoglycoside or
Ampicillin/ Vancomycin (for beta-lactam allergy) plus aminoglycoside or thirdgeneration cephalosporin (if no
enterococcus)
Adjust antibiotics according to culture results
Blood cultures positive in 20 40% of patients
Switch from parenteral to oral therapy at 48 hours after clinically well
Treat for 14 days.

Acute pyelonephritis with intrarenal, perirenal or pararenal abscess

Treatment for complicated UTI and add appropriate drainage.

Epididymitis

TMP/SMX or fluoroquinolones for at least 3 weeks to obtain adequate tissue

levels.

Acute bacterial prostatitis

TMP/SMX or fluoroquinolones for at least 4 weeks to obtain adequate tissue

levels

Chronic bacterial prostatitis

TMP/SMX or fluoroquinolones for 6 12 weeks.

Re-infection

A test of cure should be undertaken by repeat culture in pregnancy,

pyelonephritis, and complicated or relapsing UTI.
Re-infection is the relatively rapid recurrence of a UTI with the same or
different organism after cure has been documented.
Each infectious episode should be treated separately.
Consider 6 12 months of antibiotic prophylaxis (once a day oral intake of
TMP/SMX or nitrofurantoin at 1/3 to of a daily treatment dose
For patients with recurrent cystitis related to coitus, consider selfadministered single-dose antibiotics post-
coital treatment.
Antimicrobial agents

Trimethoprim-sulfamethoxazole

Trimethoprim-sulfamethoxazole has long been considered the standard of therapy for acute and recurrent
urinary tract infections because of its activity against the most common uropathogens and its low cost and
tolerability. The synergistic combination of trimethoprim and sulfamethoxazole works at two separate steps of
the bacterial folate metabolism, resulting in the inhibition of DNA synthesis.

Patients with a sulfa allergy can receive trimethoprim alone because studies showed a similar cure rate as with
trimethoprim-sulfamethoxazole. The most common side effects occurring in about 3% to 5% of patients are
skin rash, nausea, and vomiting. More serious side effects such as anemia and Stevens-Johnson syndrome are
rare, but patients should always be monitored for their occurrence. Trimethoprim-sulfamethoxazole should be
used with caution in patients with glucose-6-phosphate dehydrogenase deficiency or renal and hepatic
impairment. The serum glucose-lowering effect of sulfonylureas (such as glipizide) may be enhanced by
trimethoprim-sulfamethoxazole. Because the use of trimethoprim-sulfamethoxazole may increase the risk of
bleeding in patients taking sodium warfarin, the co administration of these agents should be closely monitored.

Fluoroquinolones

The fluoroquinolones are broad-spectrum antibiotics that inhibit topoisomerase II (DNA gyrase) and
topoisomerase IV. Although the spectrum of activity varies among the fluoroquinolones, they all have good to
excellent activity against the clinically important gram-negative uropathogens, other Enterobacteriaceae, and S
saprophyticus. Ciprofloxacin and levofloxacin are the two most commonly used fluoroquinolones for urinary
tract infections and cause minimal side effects such as nausea, diarrhea, dizziness, photosensitivity, and
headache. Products that contain cations such as magnesium, aluminum, calcium, iron, zinc, or multivitamins
with minerals may significantly decrease the absorption of the fluoroquinolones from the gastrointestinal tract.
Patients should be advised to take fluoroquinolones 2 hours before or 4 hours after ingesting any product
containing cations. Ciprofloxacin and levofloxacin may decrease the metabolism of caffeine and theophylline.
Because the coadministration of warfarin and a fluoroquinolone may result in increased anticoagulation,
patients taking this combination should be monitored. The use of fluoroquinolones is contraindicated in women
who are pregnant or breastfeeding.

-Lactams

In the past, -lactam antibiotics such as first-generation cephalosporins (cephalexin) and the aminopenicillins
(ampicillin, amoxicillin) were routinely used to treat urinary tract infections. Although the first-generation
cephalosporins and the aminopenicillins achieve high urinary concentrations, they are no longer recommended
as first-line therapy for urinary tract infections because of resistance and higher recurrence rates compared
with other agents. These agents should be used only if a urine culture documents susceptibility. However,
third-generation cephalosporins such as cefixime and cefpodoxime offer the advantage of longer half-lives,
which allows for less frequent dosing. Also, lower resistance rates to E coli have been observed with these
agents than with the first-generation cephalosporins and aminopenicillins. These agents may be options for
patients who are intolerant to trimethoprim-sulfamethoxazole or who have resistant infections.

The most common side effects of the -lactams include rash, nausea, abdominal pain, vomiting, and headache.
The -lactams inhibit bacterial wall synthesis. The use of cephalosporins and penicillins should be avoided in
patients with a history of serious -lactam allergy (anaphylaxis, hives).
Nitrofurantoin

Nitrofurantoin is available in two formulations, the macrocrystalline formulation (Macrodantin) and the
monohydrate-macrocrystal form (Macrobid). Nitrofurantoin inhibits several bacterial enzyme systems
involved with metabolism and possibly inhibits cell wall synthesis. Macrodantin requires dosing every 6 hours
whereas Macrobid requires only twice-a-day dosing. About 90% of nitrofurantoin is renally excreted through
glomerular filtration and tubular secretion. If the patient's estimated creatinine clearance is less than 0.83 mL
per second (<50 mL per minute), antibacterial concentrations attained in the urine are inadequate; therefore, this
drug should not be used. Side effects are minimal and may include malaise, cough, and dyspnea. Pulmonary
fibrosis is rare and usually associated with therapy for longer than 6 months.

Fosfomycin tromethamine

Fosfomycin is a phosphoric acid derivative used only for the treatment of uncomplicated urinary tract
infections. It is administered as a one-time 3-gram oral dose. Fosfomycin inhibits pyruvyl transferase, which is
an enzyme that catalyzes the first step in bacterial wall synthesis. Fosfomycin's spectrum of activity includes E
coli, enterococci, and Serratia, Enterobacter, Citrobacter, and Klebsiella species but does not cover S
saprophyticus. Fosfomycin is available as a powder that must be mixed with 3 to 4 oz of water before oral
administration. Overall, it is well tolerated. Side effects that may occur include diarrhea (9%), nausea, vomiting,
and esophageal discomfort.

Summary points

In the past decade, resistance of uropathogens to trimethoprim-sulfamethoxazole and trimethoprim has

increased dramatically
Three-day therapies appear to be optimal and provide similar eradication rates and a lower incidence of
side effects than 7 to 10 days of therapy
Trimethoprim-sulfamethoxazole and trimethoprim are still considered first-line therapy for
uncomplicated urinary tract infections in areas where resistance in the community is less than 10% to
20%
Fluoroquinolones should not be used as first-line drug therapy except in communities wherein resistance
to trimethoprim is greater than 10% to 20% or in patients with risk factors for resistance
In patients who have frequent bouts of recurrent uncomplicated cystitis, antibiotic prophylaxis should be
offered to prevent infections

In an excellent review article, Gupta and others outlined the treatment of uncomplicated urinary tract infections
in women (see Figure).